Yannick Béjot

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

BACKGROUND Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. METHODS In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. FINDINGS 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0). INTERPRETATION In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. FUNDING Public French National Programme for Clinical Research.

Incidence of Stroke in Europe at the Beginning of the 21st Century: The European Registers of Stroke (EROS) Investigators

BACKGROUND AND PURPOSE Comparable data on stroke incidence across European countries are lacking because previous studies have used different methods of case ascertainment, different periods of observation, and different age restrictions. METHODS Population-based stroke registers were established in 6 European countries: France (Dijon); Italy (Sesto Fiorentino); Lithuania (Kaunas); the United Kingdom (London); Spain (Menorca); and Poland (Warsaw). Standardized criteria were used among these register including overlapping sources of notification. Overall, a source population of 1087048 inhabitants was observed, ranging from 47236 in Sesto Fiorentino to 365191 in Kaunas. All patients with first-ever stroke of all age groups from the source populations were included. Data collection took part between 2004 and 2006; 4 centers collected data for a 24-month and 2 for a 12-month time period. Crude annual incidence rates were age-adjusted to the European population. RESULTS A total of 2129 patients with first stroke were registered. Median age was 73 years and 51% were female. Annual stroke incidence adjusted to the European population was found in men to be higher in Kaunas and lower in Sesto Fiorentino and Menorca and in women to be higher in Kaunas and Warsaw and lower in Sesto Fiorentino and Menorca compared with mean incidence rates. Total stroke incidence ranged in men from 101.2 per 100000 (95% CI, 82.5 to 123.0) in Sesto Fiorentino to 239.3 per 100000 (95% CI, 209.9 to 271.6) in Kaunas and in women from 63.0 per 100000 (95% CI, 48.5 to 80.7) in Sesto Fiorentino to 158.7 per 100000 (95% CI, 135.0 to 185.4) in Kaunas. Differences in prior-to-stroke risk factors were found among the populations with prevalence of hypertension highest in Warsaw and Kaunas (76% and 67%, respectively) and lowest in Menorca and Sesto Fiorentino (54% and 62%, respectively). CONCLUSIONS The risk of stroke among European populations in our study varied more than 2-fold in men and women. On average, higher rates of stroke were observed in eastern and lower rates in southern European countries.

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke

BACKGROUND Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS In a multicenter, randomized, open‐label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long‐term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet‐only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet‐only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet‐only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289.)

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats.

Although brain-derived neurotrophic factor (BDNF) plays a central role in recovery after cerebral ischemia, little is known about cells involved in BDNF production after stroke. The present study testes the hypothesis that neurons are not the unique source of neosynthesized BDNF after stroke and that non neuronal-BDNF producing cells differ according to the delay after stroke induction. For this purpose, cellular localization of BDNF and BDNF content of each hemisphere were analysed in parallel before and after (4h, 24h and 8d) ischemic stroke in rats. Stroke of different severities was induced by embolization of the brain with variable number of calibrated microspheres allowing us to explore the association between BDNF production and neuronal death severity. The main results are that (a) unilateral stroke increased BDNF production in both hemispheres with a more intense and long-lasting effect in the lesioned hemisphere, (b) BDNF levels either of the lesioned or unlesioned hemispheres were not inversely correlated to neuronal death severity whatever the delay after stroke onset, (c) in the unlesioned hemisphere, stroke resulted in increased BDNF staining in neurons and ependymal cells (at 4h and 24h), (d) in the lesioned hemisphere, beside neurons and ependymal cells, microglial cells (at 24h), endothelial cells of cerebral arterioles (at 4h and 24h) and astrocytes (at 8d) exhibited a robust BDNF staining as well. Taken together, overall data suggest that non neuronal cells are able to produce substantial amount of BDNF after ischemic stroke and that more attention should be given to these cells in the design of strategies aimed at improving stroke recovery through BDNF-related mechanisms.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Association of Vascular Risk Factors With Cervical Artery Dissection and Ischemic Stroke in Young Adults

Background— Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. Methods and Results— The study sample comprised 690 CEAD patients (mean age, 44.2±9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7±10.5 years; 39.9% women), and 1170 referents (45.9±8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥30 kg/m2) or overweightness (body mass index ≥25 kg/m2 and <30 kg/m2) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. Conclusion— These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

Trends in the incidence of ischaemic stroke in young adults between 1985 and 2011: the Dijon Stroke Registry

Background Recent data have suggested that stroke incidence in young people may be rising. In this population-based study, we aimed to determine whether the incidence of stroke in people aged <55 years old had changed over the last three decades. Methods All cases of first-ever stroke (ischaemic stroke, spontaneous intracerebral haemorrhage, and undetermined stroke) occurring in Dijon, France, from 1985 to 2011 were prospectively collected from a population-based registry. Incidence rates were calculated and temporal trends were analysed by age groups and stroke subtypes using a Poisson regression to estimate incidence rate ratios (IRR). Risk factors and premorbid treatments were analysed. Results Over the 27-year study period, 4506 patients were recorded (53% women, mean age 74.6±14.4, 10.1% aged <55 years). An increase in overall stroke incidence was noted, as was a rise in ischaemic stroke in individuals aged <55 years (IRR 1.308; 95% CI 0.982 to 1.741, p=0.066 for period 1994–2002 vs period 1985–1993, and IRR 1.697; 95% CI 1.340 to 2.150, p<0.001 for period 2003–2011 vs period 1994–2002), which was consistent for men and women. In these young patients, smoking was the most frequent risk factor (43%). Conclusions Multiple factors may account for the increased incidence of ischaemic stroke in people aged <55 years including changes in vascular risk factors, better awareness of the disease and treatment options in the population and among practitioners leading to more frequent referrals for specialised care, and improvements in stroke diagnosis. Stroke prevention must be encouraged even in young adults.

Three-month stroke outcome: The European Registers of Stroke (EROS) Investigators

Background: Contemporaneous data on variations in outcome after first-ever-lifetime stroke between European populations are lacking. We compared differences in case fatality rates, functional outcome, and living conditions 3 months after stroke within the European Registers of Stroke Collaboration. Methods: Population-based stroke registers were established in France (Dijon), Italy (Sesto Fiorentino), Lithuania (Kaunas), the United Kingdom (London), Spain (Menorca), and Poland (Warsaw). All patients with first-ever-lifetime stroke of all age groups from the source population (1,087,048 inhabitants) were included. Data collection took part between 2004 and 2006. The study investigated population variations in outcome at 3 months (death, institutionalization due to stroke, or Barthel Index below 12 points) using multivariable logistic regression analyses adjusted for age, sex, stroke severity, stroke subtype, and comorbidities. Results: A total of 2,034 patients with first-ever-lifetime stroke were included. Median age was 73 years, 52% were female. The mean weighted cumulative risk of death was 21.8% (95% confidence interval 20.0 to 23.6) with a 3-fold variation across populations. The weighted proportion of poor outcome was 41.3% (95% confidence interval 39.0 to 43.7) with a 2-fold variation across populations. Conclusion: More than 40% of patients had a poor outcome, defined as being dead, dependent, or institutionalized 3 months after stroke. Substantial outcome variations were found between populations that were explained by case mix variables in this analysis, yet a trend toward a higher risk of poor outcome was present in Kaunas.

Trends in Incidence, Risk Factors, and Survival in Symptomatic Lacunar Stroke in Dijon, France, From 1989 to 2006 A Population-Based Study

Background and Purpose— Lacunar infarcts are usually regarded as benign stroke, but population-based studies are required to assess the exact place of this stroke subtype in cerebrovascular pathology. Methods— We evaluated trends in incidence rates, risk factor profiles, and survival rates in symptomatic lacunar stroke from a prospective population-based registry from 1989 to 2006. Results— We recorded 2536 ischemic strokes. Among these, 715 (28%) were lacunar infarcts (354 men and 361 women). From 1989 to 2006, we observed a significant rise in the incidence of lacunar stroke in the 2 sexes considered together (relative risk, 1.02; 95% CI, 1.005 to 1.035; P=0.007), whereas the variation was not significant in either men or women when considered separately. Incidence rates significantly increased in young patients under 65 years old (relative risk, 1.049; 95% CI, 1.0175 to 1.0817; P=0.002). Concerning the distribution of cerebrovascular risk factors, lacunar stroke differed from nonlacunar stroke only with regard to the lower prevalence of a history of atrial fibrillation in the former (P<0.001). For lacunar infarcts, survival rates were 96% at 1 month (95% CI, 0.94 to 0.97), 86% at 1 year (95% CI, 0.83 to 0.89), and 78% at 2 years (95% CI, 0.75 to 0.81) and were significantly higher than those for nonlacunar stroke (hazard ratio, 2.05; 95% CI, 1.70 to 2.47; P<0.001). Conclusion— Our results suggest a significant increase in the incidence rates of lacunar stroke with a relatively good short-term prognosis in terms of survival. The association among hypertension, diabetes mellitus, and lacunar stroke was no stronger than the association between these 2 risk factors and nonlacunar stroke.